IntroductionIt has been shown that cardiac functions begin to deteriorate in growth hormone (GH) deficiency even in childhood. However, little is known about how GH deficiency affects arrhythmogenesis. The aim of this study was to evaluate the parameters of P wave dispersion (Pd), QT dispersion (QTd), corrected QT (QTc) dispersion (QTcd), T wave peak-to-end (Tp-e) interval, Tp-e/QT ratio, and Tp-e/QTc ratio in children with GH deficiency. This study also aimed to evaluate the relationship of these parameters with insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3).MethodIn the study, records of children diagnosed with GH deficiency in Adana City Training and Research Hospital Pediatric Endocrine Outpatient Clinic between September 2021 and December 2022 were retrospectively reviewed. The control group consisted of children in the same age group who applied to the Emergency Outpatient Clinic with a complaint of chest pain and no pathological finding was detected. The electrocardiograms (ECGs) of all patients were retrospectively evaluated.ResultsThere were a total of 82 children in the study, 41 of whom were diagnosed with GH deficiency and 41 in the healthy control group. The age and male/female ratio of children with GH deficiency were similar to those in the control group (p>0.05). There were 27 (66%) children with complete GH deficiency and 14 (34%) children with partial GH deficiency. P wave dispersion was similar in both GH-deficient children and control group children. It was also similar in children with complete and partial GH deficiency (p>0.05). QT and QTc dispersions were found to be increased in children with GH deficiency, although not statistically significant, compared to the control group (p>0.05). Tp-e interval, Tp-e/QTmax , and Tp-e/QTcmax  ratios were increased in children with GH deficiency compared to the control group . QT and QTc dispersion, Tp-e interval, Tp-e/QTmax, and Tp-e/QTcmax ratios were found to be increased in children with complete GH deficiency compared to children with partial GH deficiency, but the difference was not significant (p>0.05). No correlation was found between these ECG parameters and IGF-1, IGFBP-3, and peak GH levels after stimulation tests (p>0.05).ConclusionWe found in our study that the Tp-e interval was longer and Tp-e/QT and Tp-e/QTc ratios were increased in children with GH deficiency. These results suggest that the risk of ventricular arrhythmias in children with GH deficiency may start to increase from childhood. However, further prospective studies are needed to confirm our results. Growth hormone (GH) has effects on many systems as well as stimulating growth in children. In addition to cardiac growth in the cardiovascular system, it plays a role in the regulation of cardiac structure and function . Both GHGrowth hormone deficiency is characterized by significant growth retardation, slowing of growth rate, retardation in bone age, and low GH level despite spontaneous and pharmacological stimulation, when there is no other reason to explain the short stature ,8. It isIn experimental studies, it has been reported that GH exerts cytoprotective effects after coronary artery occlusion and reduces local myocardial norepinephrine release and arrhythmogenesis . In studA surface electrocardiogram (ECG) is an easily accessible test that provides a rapid assessment of cardiac electrophysiology and can be used to assess arrhythmic risk . In the The aim of this study was to evaluate the parameters of P wave dispersion, QT dispersion, QTc dispersion, Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio in children with GH deficiency. In addition, the study is also aimed at evaluating the relationship of these parameters with IGF-1 and IGFBP-3.In the study, records of children diagnosed with GH deficiency in Adana City Training and Research Hospital Pediatric Endocrine Outpatient Clinic between September 2021 and December 2022 were retrospectively reviewed. GH deficiency was diagnosed according to clinical and auxology criteria. The diagnosis of GH deficiency was considered in a child with short stature (height below 3 standard deviation (SD) or less than 2 SD and annual growth rate below 2 SD) after excluding other causes of growth retardation . GH provocation tests (L-dopa and insulin tolerance test) were performed. A peak GH value of <10 µg/L after two separate GH provocation tests was defined as GH deficiency . ChildreECG recordings were made at a rate of 25 mm/second, with an amplitude of 1 mV, and with 12 standard leads containing at least six QRS complexes for each lead. Measurements in all leads were performed manually. The difference between the longest P wave (Pmax) and the shortest P wave (Pmin) was considered as the P dispersion (Pd=Pmax-Pmin). The time between the onset of the QRS complex and the point where the descending branch of the T wave cut the isoelectric segment was taken as the QT interval. Leads in which T wave could not be detected were excluded. QT dispersion was defined as the difference between the longest (QTmax) and the shortest (QTmin) QT interval (QTd=QTmax-QTmin). Bazett’s formula (QTc=QT/√RR) was used for QTc. QTc dispersion was similarly determined as the difference between the longest QTc (QTcmax) interval and the shortest QTc (QTcmin) interval. The Tp-e interval was defined as the interval from the peak of the T wave to the end of the T wave. Tp-e interval measurements were made from lead V5. In addition, Tp-e/QTmax and Tp-e/QTcmax ratios were calculated.Approval was obtained from the Non-Invasive Clinical Research Ethics Committee of Pamukkale University (10.01.2023/01) before conducting the study.The Statistical Package for the Social Sciences (SPSS) for Windows version 20  was used for the statistical evaluation of data. Continuous variables were given as mean±standard deviation (minimum-maximum), and categorical variables were given as number (percentage). Kolmogorov-Smirnov and Shapiro-Wilk tests were used to determine the normal distribution. In the comparison of independent data, Student’s t-test was used for parametric data and the chi-square test was used for the comparison of categorical variables. The correlation of continuous variables was evaluated using Pearson correlation analysis, and p<0.05 was accepted as statistically significant.2, respectively, in children with GH deficiency. On the other hand, these values were 140.5±21.7 (100-184) cm, 37.9±16.7 (15-74) kg, and 17.9±3.5 (13.2-25.51) kg/m2, respectively, in the control group. The height and body weight of children with GH deficiency were significantly lower than the control group (p=0.001), and the body mass index was at the low threshold (p=0.05). While height standard deviation score (SDS) and body weight SDS were significantly lower in children with GH deficiency (p<0.001), no significant difference was found in body mass index SDS (p=0.074)  . The maximum and minimum P wave intervals and P dispersion were similar in children with GH deficiency and in the control group (p>0.05) Table . There wWhen the children with GH deficiency were divided into two groups according to the results of the provocation tests, there were 27 (66%) children with complete GH deficiency and 14 34%) children with partial GH deficiency. There was no significant difference between children with complete and partial GH deficiency in terms of age, gender, height SDS, body weight SDS, and body mass index SDS (p>0.05), and heart rates were also found to be similar (p>0.05) , and structural remodeling of the left atrium has been demonstrated that may mediate the increased risk of AF in patients with GH deficiency ,23,24. PExperimental studies have shown that IGF-1 regulates sarcolemmal potassium channel activity and late sodium current in rat cardiomyocytes, thereby affecting cardiac repolarization and QTc ,27. In aIGF-1 is thought to protect cardiac myocytes from arrhythmogenesis and apoptosis by activating PI3K/Akt intracellular signal transduction . ChangesThe main limitation of this study is that it is a retrospective study with a relatively small sample size. Other limitations are the lack of echocardiographic evaluation and evaluation of children with GH deficiency after treatment. Therefore, further prospective studies with larger populations are needed to confirm our results.We found in our study that the Tp-e interval is longer and the Tp-e/QT and Tp-e/QTc ratios are increased in children with GH deficiency. These results suggest that the risk of ventricular arrhythmias in children with GH deficiency may start to increase from childhood. However, further prospective studies are needed to confirm our results.


When modeling transcranial magnetic stimulation (TMS) in the brain, a fast and accurate electric field solver can support interactive neuronavigation tasks as well as comprehensive biophysical modeling.i.e., non-iterative) TMS solver that can accurately determine global TMS fields for any coil type everywhere in a high-resolution MRI-based surface model with ~200,000 or more arbitrarily selected observation points within approximately 5 sec, with the solution time itself of 3 sec.We formulate, test, and disseminate a direct (The solver is based on the boundary element fast multipole method (BEM-FMM), which incorporates the latest mathematical advancement in the theory of fast multipole methods – an FMM-based LU decomposition. This decomposition is specific to the head model and needs to be computed only once per subject. Moreover, the solver offers unlimited spatial numerical resolution.Despite the fast execution times, the present direct solution is numerically accurate for the default model resolution. In contrast, the widely used brain modeling software SimNIBS employs a first-order finite element method that necessitates additional mesh refinement, resulting in increased computational cost. However, excellent agreement between the two methods is observed for various practical test cases following mesh refinement, including a biophysical modeling task.The method can be readily applied to a wide range of TMS analyses involving multiple coil positions and orientations, including image-guided neuronavigation. It can even accommodate continuous variations in coil geometry, such as flexible H-type TMS coils. The FMM-LU direct solver is freely available to academic users. For TMS to be a more effective and personalized therapeutic tool, it is crucial to accurately simulate the induced electric field (E-field) distribution in the brain. For interactive E-field based TMS neuronavigation, the E-field should be updated and displayed fast enough to provide the operator with a sense of real-time interaction.There are several time scales to consider. First, most real-time visualization applications have a minimum update rate of around 15–30 frames per second (fps) to have a smooth and continuous experience; this allows for approximately 30–60 ms for coil position update, E-field solution update, and image rendering. The second time scale of relevance relates to the pace at which a human or a robot  could moOver the past two years, significant progress has been made with regard to excellent real-time high-resolution solvers for TMS field modeling ,6],7],,[7],6],,6],This study aims to introduce a direct accurate TMS solver that can output TMS fields from any coil and anywhere in a high-resolution head model within ~3–5 sec. This solver is based on the boundary element fast multipole method or BEM-FMM ,9],10],[10]9],9], and the e.g., . As. As17]. BEM-FMM) ,9],10],[10]N is,[10]N isBEM-FMM)  utilizesBEM-FMM) ,20] and andN is BEM-FMM) .multiple right-hand sides. Along with this, fast direct solvers could be useful when exploring low-rank perturbations of the head geometry (and/or tissue conductivities) and, hence, the system matrix. Updating the solution in such cases requires only a few applications of A−1 or a fast update of the inverse itself ..multipleA−1 at a cost of the order O(N) or O(NlogpN), for modest p. To construct the first fast direct TMS solver, we apply one such scheme . Th. Thρ(r) d/stored ,9],10],[10]ρ(r),[10]ρ(r)d/stored .A. In other words, a compressed approximation of A−1 is found directly so that a direct solution x = A−1b is attempted, without using an iterative method and for multiple right-hand sides, b. While matrix A is determined by the head model, the right-hand sides describe coil fields. This is the compression algorithm of Ref. . Th. ThM1HANitioning .M1HAND target. However, this model is manually refined in the region of interest (ROI) so that its overall size is 1,8 M facets. In all cases, the default SimNIBS conductivity parameters [Finally, we test a healthy subject scanned at Max Planck Inst. for Human Cong. & Brain Sciences Leipzig, Germany with the MagVenture CB65 coil and the same left rameters  have bee2.4.Errortotal, and the error in the magnitude of the E-field, Errormagt denotes the total E-field in the head which is a sum of the primary field and the secondary field. As a ground truth, an iterative BEM-FMM solution with 54 million facets , the FMM precision [Both accuracy and speed are tested. Two error types are considered: the relative error in the vector E-field, recision  of 1e-6,3.3.1.For the default Ernie model example  of the FThe iterative BEM-FMM solution in 3.2.M1HAND of the left hemisphere. Along with this, the Ernie model provided with SimNIBS FEM software, segmented with the standard headreco settings, and the default coil type/position is also tested. The superscript denotes standard deviation.3.3.The method speed was tested using four nearly identical workstations with Intel(R) Xeon(R) Gold 6348 CPU @ 2.60GHz, 512 GB RAM, 56 cores, OS Windows Server 2022 Standard and the common MATLAB 2021b platform. Equivalent SimNIBS v3.2.6/4.0 execution times on high-performance workstations were approximately 40 s. SimNIBS run times on a 2.3 GHz laptop are faster – approximately 30 s.3.4.dI/dt = 9.4e7 A/s. The computational sequence for any type of output from As the first computational example, 3.5.flexible, and it changes its shape when continuously aligned with the patient’s head. Therefore, step I in As a second example, 4.4.1non-distinguishable from the accuracy of BEM-FMM given the FMM precision level of 1e-4 or better used for constructing the compressed inverse. In this case, the factorization data stored in MATLAB workspace have the size of approximately 50 Gigabytes; their creation requires approximately 70 min. The direct solution – step II in When the FMM precision level is reduced to 1e-3, the factorization data will have the size of 30 Gigabytes, their generation requires approximately 40 min, and the direct solution  on the coil axis as shown in dI/dt, of a MagStim 70 mm coil (the SimNIBS coil model is used) for the default NeMo-TMS pulse form. Three intracortical neural cells  from a multi-scale toolbox Neuron Modeling for TMS (NeMo-TMS)  were pla4.4.The present method has been tested on four multicore (32 to 56 cores) 2.6 GHz workstations. The minimum required RAM is approximately 64 Gigabytes. The FMM-LU factorization of the head-model specific system matrix requires approximately 40 min. The present method cannot run on a standard laptop.As of today, neither BEM-FMM nor FMM LU are in position to handle macroscopic medium anisotropy. If the anisotropic part of the volume conductor model would be perfectly aligned and have the matching resolution, the error would be on the order of 10% with respect to the isotropic case as our computations for the healthy subject scanned at Max Planck Inst. for Human Cong. & Brain Sciences Leipzig, Germany show. However, the estimate of the anisotropy conductivity tensor based on the diffusion tensor imaging data is subject to its own challenges.5.The direct TMS solver suggested in this study can determine global E-fields in modern high-resolution head models in approximately 5 seconds, which approaches the speed of single-pulse TMS motor mapping. There are no limitations on coil positions, coil types, coil deformations, ROI sizes, and ROI locations. For the standard head model, solver’s numerical accuracy is better than the accuracy of the widely used first-order FEM software when the isotropic head models are used. The FMM LU method can thus be employed to accelerate optimization problems in which a large number of coil configurations have to be simulated and a very large number of field values have to be computed. For example, approximately 24 hours would be necessary to accurately compute intracortical fields at 200,000 observation locations anywhere inside the brain volume for 1,000 TMS coil positions and 20 orientations per position.The method could be readily expanded to other types of brain stimulation. Ref.  presents


All coronary artery disease (CAD) patients do not benefit equally of secondary prevention. Individualized intensity of drug therapy is currently implemented in guidelines for CAD and diabetes. Novel biomarkers are needed to identify patient subgroups potentially benefitting from individual therapy. This study aimed to investigate endothelin-1 (ET-1) as a biomarker for increased risk of adverse events and to evaluate if medication could alleviate the risks in patients with high ET-1.A prospective observational cohort study ARTEMIS included 1946 patients with angiographically documented CAD. Blood samples and baseline data were collected at enrollment and the patients were followed for 11 years. Multivariable Cox regression was used to assess the association between circulating ET-1 level and all-cause mortality, cardiovascular (CV) death, non-CV death and sudden cardiac death (SCD).Here we show an association of circulating ET-1 level with higher risk for all-cause mortality , CV death, non-CV death and SCD in patients with CAD. Importantly, high intensity statin therapy reduces the risk for all-cause mortality  and CV death  in patients with high ET-1, but not in patients with low ET-1. High intensity statin therapy does not associate with reduction of risk for non-CV death or SCD.Our data suggests a prognostic value for high circulating ET-1 in patients with stable CAD. High intensity statin therapy associates with reduction of risk for all-cause mortality and CV death in CAD patients with high ET-1. Patients with coronary artery disease (CAD) – in which the blood vessels supplying the heart become blocked - need careful management to prevent adverse outcomes related to their disease, such as a heart attack or sudden cardiac death. Identification of markers in the blood to predict adverse outcomes would help to improve the care of patients with CAD. Here, we find that higher circulating levels of endothelin-1 (ET-1), a protein secreted normally to maintain blood pressure, associate with greater risk of death in CAD patients. Cholesterol-lowering statin therapy used at high intensity (high dosage) can counteract the increased risk of death observed in CAD patients with high ET-1. Therefore, circulating ET-1 level could be used as a marker to predict the risk of death in CAD patients, and an indication for high intensity statin therapy. Our findings could help clinicians to improve the management of patients with CAD. Lin et al. report an association between increased circulating endothelin-1 levels and higher mortality risk in patients with stable coronary artery disease. High intensity statin therapy is associated with a reduced risk of all-cause mortality or cardiovascular death in patients with high endothelin-1 levels. Several biomarkers have been studied in this respect, but a comprehensive risk assessment tool is lacking. While some patient groups in this population have been identified and different target levels and therapy regime have been implemented (e.g. diabetes in secondary prevention5), there is a need to construct a robust group of risk markers with enough power to guide the therapy among high-risk patients.Secondary prevention among patients with coronary artery disease (CAD) has improved immensely during the last few decades. However, not all patients are benefitting equally from secondary prevention and accessible markers for identification of patients at higher risk are direly neededA and ETB receptors and serves a role in maintaining basal level of vascular tone, contributing to systemic and pulmonary artery resistance. In addition to being a potent vasoconstrictor, ET-1 has pro-inflammatory and mitogenic effects promoting vascular smooth muscle growth, cardiac hypertrophy and myocardial fibrosis6. Selective ETA and dual ETA/ETB receptor antagonists are in clinical use for treatment of primary pulmonary arterial hypertension7 and ETA receptor blocker atrasentan has shown efficacy in reducing the risk of renal events in patients with diabetes and chronic kidney disease8.Endothelin-1 (ET-1), secreted primarily by endothelial cells and vascular smooth muscle cells, functions through ET9 as well as in patients with stable CADs10. In the present study, we identify an association of circulating ET-1 levels and mortality among patients with stable CAD in over 10-year follow-up. Additionally, we find that high intensity statin therapy holds the potential to offset the increased mortality associated with elevated ET-1.Prior studies have shown prognostic role for ET-1 in patients with acute myocardial infarction12, a prospective observation study. The ARTEMIS study was conducted at Oulu University Hospital’s Division of Cardiology during 2007–2012, after enrollment visit, the follow-up was through phone call. The inclusion criteria for the study were angiographically documented CAD with or without T2D. CAD was defined as more than one vessel with >50% stenosis detected by coronary angiography, and the diagnosis of T2D was done according to the World Health Organization standard .Patient blood samples were obtained from the ARTEMIS study The exclusion criteria included left ventricular ejection fraction (LVEF) < 35%, NYHA class IV, pregnancy, life expectancy <1 year and end-stage renal failure requiring dialysis. Blood and echocardiographic parameters were collected at the enrollment visit, the time of which was at least 3 months after the coronary angiography or the last revascularization.N = 618) females, 42.8% (N = 833) participants with type 2 diabetes (T2D), with an average age of 67 years IQR .In total, there were 1946 patients in the present study, and ET-1 concentration was acquired from 1945 patients. During the follow-up (mean 7.86 ± 2.12 years), 218 participants died with 116 due to CV death and 102 for non-CV death. 50 out of 116 CV deaths were SCDs. The overall population consisted of 31.8%  death, non-CV death and sudden cardiac death (SCD). SCD was defined by a witnessed death within one hour of the onset of symptoms, or unwitnessed death where the patients was last seen alive and stable within 24-h before found deceased.All laboratory tests were carried out with standardized methods after 12-h overnight fast. Biomarkers for inflammation, cardiac function and renal function were acquired from the blood and urine samples and analyzed in the Oulu University Hospital laboratory. ET-1 was measured from the serum samples by using Quantikine Endothelin-1 ELISA kit .The serum samples were obtained by allowing the blood to clot for 30 min at room temperature, followed by centrifugation at 2000 g for 10 min. The serum was then aliquoted and stored at −20 °C until analyzed. Samples had not been thawed prior the ET-1 level analysis. The interval between the sample collection and ET-1 analysis was 6–12 months.The analyses for ET-1 levels were performed manually and in duplicates for each sample. According to manufacturer, the intra-assay precision for the assay is 1.9%–4.0% and the inter-assay precision is 5.3%–7.6%. The sensitivity of the assay, assessed by minimum detectable dose of ET-1, was from 0.031 to 0.207 pg/mL, with a mean of 0.087 pg/mL in 34 samples.t test. Otherwise, values are expressed as median [interquartile range (IQR)], assessed with non-parametric Wilcoxon rank-sum comparison. Categorical data is expressed as counts (percentage) and analyzed with chi-square (χ2) test. When expected frequency was below 5, Fisher-exact test was applied instead.To select the approach of description of scalar variables, normality test was conducted. If the scalar variable followed normality, values are expressed as mean ± SD and examined by Student’s 14 curve analysis was conducted to obtain the optimal cutoff value of ET-1 to predict all-cause mortality with fitting into logistic regression. The optimal threshold was defined by maximizing the difference between true positive rate (sensitivity) and false negative rate (1-specificity), i.e., Youden index.Receiver-operating characteristic (ROC)Univariable and multivariable Cox proportional hazard (PH) regression models were used to estimate hazard ratio and 95% confidence interval (95% CI) of variables. In model 1, traditional clinical risk factors age, sex, T2D, body mass index (BMI), systolic blood pressure (sysBP), and B-type natriuretic peptide (BNP) were included into the variable selection. In model 2, the following clinically relevant variables were assessed for adjustment: age, sex, T2D, BMI, sysBP, BNP, diastolic blood pressure (diaBP), smoking, prior MI, prior percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), and NYHA classification. Based on model 2, model 3 additionally included creatinine clearance, left ventricular ejection fraction (LVEF), percentage of glycated hemoglobin A1c (%GHbA1C), low-density lipoprotein (LDL), insulin, high-density lipoprotein (HDL), total cholesterol and triglyceride levels. To address possible confounding effect of other medications, the use of statins was adjusted for age, sex, T2D, NYHA, ACEIs, ARBs, β-blockers, CCBs and diuretics (model medications).16 was applied to acquire the best set of variables in each model. The AIC selected variables according to both fitness and complexity (over-fitting) of a model by introducing a penalty for each inclusion of variable. The single variable that reduced AIC the most was the first variable retained in the model. Addition of a variable to the model required the added variable together with previously retained variables to outperform the last-step retained variables. Harrell concordance index (C-index) was also calculated to assess the ability of the model to discriminate outcomes. Alternatively, in model S4, univariable CoxPH was used to calculate variable significance, and if a result of p < 0.05 was obtained, variable was included for multivariable adjustment. The set of variables used for selection was the same as in model 3.In models 1–3 and model medication, a stepwise forward selection of candidate variables based on Akaike Information Criterion (forward-AIC)18 survival curve was statistically evaluated by log-rank test. For quartile analysis, the relation of ET-1 level to the outcome was analyzed by categorizing quartiles as continuous variables. In model 3, collinearity was assessed by computing variance inflation factor19, which was no greater than 2 for each independent variable.The PH assumption was examined by inspecting log-minus-log (LML) plots against time for both high ET-1 and low ET-1 groups. If LML crossed and thus violated assumption, log-rank test was applied for survival analysis. Kaplan-Meierp < 0.05, and all tests were 2-sided. For multiple comparisons between ET-1 level and risk of endpoint events, p-value < 0.0125 (0.05/4) was defined statistically significant for each of the four endpoints. In analysis for association of intensity of statin therapy with risk of all-cause mortality and CV death, the p-value < 0.025 (0.05/2) was defined statistically significant. Excel 2016 and SPSS 25 were used for data collection. Kaplan-Meier survival plot were constructed by lifelines module of Python, and all statistical comparison were performed with R version 4.0.4.The statistical significance was defined as 21The study protocol was approved by the ethics committee of the Northern Ostrobothnia Hospital district, and written informed consents were obtained from all the patients when recruited during 2007–2012. The study complied with the Declaration of HelsinkiFurther information on research design is available in the In total there were 1946 patients in the study, and ET-1 concentration was acquired from 1945 patients, with a median concentration of 1.51 pg/mL (IQR 1.25–1.88 pg/mL). Area under the curve (AUC) from ROC analysis indicated that the accuracy derived from ET-1 as continuous variable to predict all-cause mortality was 0.684 (95% CI: 0.646–0.722), and the best threshold (maximum sensitivity and specificity) was 1.585 pg/mL Fig. . The spevs 66 IQR , p < 0.0001), were more often women  and had more frequently T2D  , Angiotensin II receptor blockers (ARBs), diuretics and calcium channel blockers (CCBs). The use of lipid lowering agents or β-adrenergic blockers (β-blockers) showed no difference between high and low ET-1 groups.p < 0.0001), CV death , non-CV death  and SCD  , CV death, non-CV death and SCD (Table p < 0.001), CV death , non-CV death  and SCD .In each of the three models, patients in high ET-1 group remained at significantly higher risk for all-cause mortality  and non-CV death (trend p < 0.001), but not for CV death and SCD. Patients belonging to the fourth quartile (Q4) of ET-1 concentration held significantly higher risk for all-cause mortality and non-CV death   and re-assigned them to low, moderate or high intensity statin groups based on the intensity of therapy13. The use of statins was compared to those who did not use lipid-lowering agents . The basic characteristics of selected patients in each group are shown in Table We further investigated for a potential medical therapy that could offset the increased mortality associated with high circulating ET-1 levels. Kaplan-Meier survival curve Fig.  revealedp = 0.02) and CV death , but not with non-CV death or SCD. However, such effect on all-cause mortality and CV death was not observed in low ET-1 group . Patients in both moderate statin  and high statin  groups had reduced risk for CV death. After multivariable adjustment (Table p = 0.004) and CV death  compared to those who did not take statins. The risk reduction for CV death in moderate statin subgroup was 62%   showed that the reduction of risk conferred by the use of high and/or moderate intensity statins was independent from the use of ACEIs, ARBs, β-blockers, CCBs or diuretics  has shown a role for ET-1 in predicting CV death and heart failure in patients with stable CAD23 and also functions as a key regulator of contractility and hypertrophic response in the left ventricle25. Dysregulation of ET-1 has been observed in patients with symptomatic atrial fibrillation, and restoration of sinus rhythm after pulmonary vein isolation was associated with reduced ET-1 level in these patients26. Interestingly, despite being an essential vasoconstrictor, ET-1 can also induce arrhythmia irrespective to myocardial ischemia28. Therefore, ET-1 may act as an intrinsic arrhythmogenic factor with a distinct electrophysiological properties27. ET-1 associated arrhythmias show no change on conduction time27, but may be attributed to its potential to prolong the cardiac action potential duration29. Several mechanisms have been proposed for ET-1 related arrhythmogenic action, including altered Ca2+ mobilization and inward K+current29.ET-1 has been regarded the most potent vasoconstrictor identified in human31 The Sabatine study included 16.2% of patients with T2D10, whereas the present study, designed to study and identify risk markers between CAD patients with and without T2D, constitutes 42% of population with T2D. Given that T2D is essentially a microvascular disease, the role of ET-1, a potent vasoconstrictor, may be overestimated in the present study. However, after adjustment with four different models, ET-1 remained an independent risk factor regardless of T2D. The current findings thus support the prognostic value for high circulating ET-1 also in CAD patients with T2D. Of note, the majority of population in both Sabatine study and our study consisted of male patients . The sex imbalance in both studies indicates a need for research with focus on females to address women’s health.T2D is a risk factor for CV diseases and it’s incidence has been rising between 1996–201610 both show prognostic value for high ET-1 in patients with CAD, while a recent study did not find predictive value for ET-1 in the development of CAD32. Analysis for circulating ET-1 concentration did not associate with the extent of CAD and plaque phenotype in stable chest pain patients without a history of CAD but with an intermediate pre-test probability of obstructive CAD32.The current study and previous study34. The relative risk reduction with statins across populations is proportional to the absolute reduction in LDL, and the greatest absolute benefit is achieved in patients with the highest baseline risk35. Apart from high LDL, dysglycemia and other lipoprotein abnormalities, relatively little is known of other biological factors that may affect the benefit of an individual patient from statin therapy.The statins have shown remarkable efficacy in reducing LDL, a well-established risk factor for atherosclerotic cardiovascular disease, and in both primary and secondary prevention of cardiovascular events10. In the current study cohort, 25–45% of patients were on ACEI/ARB therapy and moderate to high intensity statin therapy was observed to reduce the risk for CV death in high ET-1 group by more than 50% independently from ACEI/ARB therapy. Importantly, our data show that treatment of patients with high intensity of statins reduces the risk for all-cause mortality and CV death in high ET-1 group but not in low ET-1 group. Patients with a higher absolute risk are likely to benefit the most from any risk reduction, including statin therapy35. On the other hand, the majority of vascular events occur in patients at lower risk as they are much larger in numbers, and an absolute LDL reduction (mmol/l) results in at least as large relative risk reduction of major vascular events in low-risk individuals36. Data from the current study suggests that among these patients at high risk, high circulating ET-1 levels can be used to stratify patients who will benefit the most from the statin therapy. We further find that the benefit is only associated with moderate and high intensity statin therapy. Additional studies are needed to investigate if the beneficial effect of statin therapy in patients with high ET-1 remains in follow-up of patients treated with statins according to the current LDL-C goals.Interestingly, we find that high intensity statin therapy reduces the high ET-1 associated risk for all-cause mortality and CV death, but not risk for non-CV death or SCD. Therefore, the risk reduction in all-cause mortality by high intensity statin therapy could logically mainly stem from decreased risk for CV death. Sabatine study showed that ACEI treatment reduces the risk for CV death or heart failure by approximately 40% in patients in highest ET-1 quartile37. In the present study, the risk for all-cause mortality and CV death was attenuated by high intensity statin treatment in high-ET-1 group but not in low ET-1 group. However, circulating ET-1 levels were not altered by statins irrespective of dosage. Therefore, it is unlikely that protection conferred by statins in patients with high ET-1 is due to decrease in ET-1 levels. We assigned the patients to statin groups according to the potential of each statin to lower the LDL levels. While the patients on statin therapy had lower LDL levels than patients without lipid-lowering therapy, the LDL levels in patients on statins were similar irrespective of the intensity of the therapy. It is therefore likely that an additional mechanism other than LDL lowering contributes to the protective effect of statins in patients with high ET-1. Prior study has shown that statins can inhibit ET-1 -induced vascular contraction and DNA synthesis in vascular smooth muscle cells, which might partially explain the beneficial effects in patients with high circulating ET-138. LDL-independent anti-oxidation, anti-inflammatory effect, increased vaso-relaxation through enhancing NO bioavailability and possible regulation of endothelial function may also account for salutary effect of statins40. Besides, given that statins are a class of HMG-CoA reductase inhibitors, therefore all intermediate products along mevalonate pathway may also be affected by treatment with statins, which can produce an effect not caused but associated with LDL reduction.Prior meta-analysis indicates that statins can reduce the levels of circulating ET-1 irrespective of intensity and durationAs an observational study, despite that we attempted to rule out important confounders with adjustments, there might be confounders beyond observation or being excluded for adjustment due to selection, which may affect the association identified here.The population in this study is well defined, but unfortunately there are no measurements of cholesterol level or ET-1 level or information on the intensity of statin treatment at follow-up. Therefore, it requires cautious interpretation of the observed association of statin therapy with attenuated risk. Moreover, while we observed association of high ET-1 with increased risk of mortality, the current data does not allow to determine if high ET-1 was also a cause for higher risk of death, which would suggest potential for ET-1 receptor antagonists to reduce mortality in CAD patients with high ET-1.Data from this observational cohort study shows that increased ET-1 concentration is associated with increased risk for all-cause mortality, CV death, non-CV death and SCD. Analysis of ET-1 levels may thus have prognostic value and be of benefit in identifying patients that should be subjected to more intensive therapy. Moreover, our data shows that high intensity statin therapy can substantially reduce the risk for all-cause mortality and cardiovascular death in stable CAD patients with high circulating ET-1. Given that the present study was hypothesis generating, independent studies with adequate power and randomization are warranted to validate the findings.Description of Additional Supplementary FilesSupplementary InformationSupplementary Data 1Supplementary Data 2Supplementary Data 3Peer Review FileReporting Summary


Journal of the American Academy of Dermatology (JAAD) were also described [JAMA Dermatology [JAMA-D], and American Journal of Clinical Dermatology [AJCD]). On July 24, 2022, the data was retrieved from the Scopus database, and the analysis was performed on RStudio (Bibliometrix/Biblioshiny) software . We only analyzed research articles and excluded the year 2022. Scopus has been covering JAAD, JAMA-D and AJCD since 1979, 2013 and 2000, respectively. In total:Recently in dermatology, the most influential scientists were reported ,2. Similescribed . In thisJAAD published 17,065 research articles. A total of 93 authors published at least 30 articles . In these publications, the authors were from 2307 universities in 65 countries.JAMA-D has published 1200 articles, of which 5975 authors from 1900 universities in 56 countries have contributed.AJCD has published 492 articles. In all publications, 1866 authors were from 838 universities in 45 countries.During the analysis, authors were included from JAMA-D and AJCD if they had published at least 5 research articles.2 or more citations. A g-index of 10 indicates that the top 10 publications have been cited at least 100 times (102). The m-quotient (or m-index) considers both the h-index and the number of years. The m-index can be obtained by dividing the h-index by the number of years since the first publication of an author. For example, an h-index of 10 for an individual over 5 years means that the m-quotient is 2.There are several bibliometric indicators that can be used for analysis. For example, the h-index considers both the number of publications and citations. In other words, a dermatologist with 5 articles with 5 or more citations (each) will have an h-index of 5. The g-index is another interesting indicator. It represents the highest number “g” of articles that together received gOur results differed from earlier reports -3, as thThe major limitations of this letter are name changes  and duplication of common names (authors and universities), which are not addressed. This may affect the ranking. We only relied on Scopus; other databases were not included in this study.


Zn-MOF ([Zn(L)2(bpa)(H2O)2]·2H2O, H2L = 5-(2-cyanophenoxy) isophthalic acid has been prepared via a low-cost, general and efficient hydrothermal method. It is worth noting the structural features of Zn-MOF which exhibit the unsaturated metal site and the main non-covalent interactions including O⋯H, N⋯H and π-π stacking interactions, which lead to strong antibacterial and good tetracycline degradation ability. The average diameter of the Zn-MOF inhibition zone against Escherichia coli and Staphylococcus aureus was 12.22 mm and 10.10 mm, respectively. Further, the water-stable Zn-MOF can be employed as the effective photocatalyst for the photodegradation of tetracycline, achieving results of 67% within 50 min, and it has good cyclic stability. In addition, the photodegradation mechanism was studied using UV-vis diffuse reflection spectroscopy (UV-VIS DRS) and valence-band X-ray photoelectron spectroscopy (VB-XPS) combined with the ESR profile of Zn-MOF, which suggest that ·O2− is the main active species responsible for tetracycline photodegradation. Also, the photoelectric measurement results show that Zn-MOF has a good photocurrent generation performance under light. This provides us with a new perspective to investigate Zn-MOF materials as a suitable multifunctional platform for future environmental improvement applications.A reported water-stable  Pathogens have a high incidence rate and mortality, which directly threaten human health and the development of the ecological environment ,2,3. For2+ can promote cell growth and differentiation, and a high concentration of Zn2+ has certain antibacterial abilities. However, pure zinc does not display activity in vitro, and Zn2+ released by pure zinc is not enough to provide sufficient antibacterial activity [Metal–organic frameworks (MOFs) are an important class of compounds in which organic bridging ligands connect metal ions or metal-containing nodes to form a three-dimensional coordination network with potential voids ,15. The activity . TherefoZn-MOF has antibacterial properties and good photocatalytic degradation performance for tetracycline. The active substances easily produced by the catalyst were characterized by ESR and the mechanism of photocatalytic degradation was revealed. Finally, we also studied the photoelectric response performance.Based on these questions, we used a case of water-stable Zn-MOF as previously reported by our research group  to studyZn-MOF had inhibitory effects on both Escherichia coli and Staphylococcus aureus. The average diameter of the inhibitory zone of Escherichia coli was 12.22 mm, and that of Staphylococcus aureus was 10.10 mm, as shown in Escherichia coli and Staphylococcus aureus may be due to the fact that the cell wall of Staphylococcus aureus (Gram-positive bacteria) is thicker than that of Escherichia coli (Gram-negative bacteria). This makes it more difficult for Zn-MOF to enter the cells of Staphylococcus aureus, thus preventing the bacterial structure from being destroyed.The results showed that Zn-MOF in this work. First, the photocatalytic performance of Zn-MOF was tested, and the photolysis efficiency reached about 67% within 50 min  = kt, where k, Ct and C0, respectively, represent the apparent rate constant of the reaction, the instantaneous concentration at time t and the initial concentration of tetracycline [Zn-MOF can be as high as 0.02627 min−1, while that of the control group is 0.0024 min−1, which represents a ten-fold increase. The results indicate that Zn-MOF has potential application value in removing tetracycline from an aqueous solution.However, in a blank control test, only negligible tetracycline degradation was observed in the absence of a photocatalyst a. In addacycline . It is fZn-MOF has good stability. At the same time, as shown in prior research [Cyclic stability is an important factor in evaluating the application of photocatalysts. Therefore, the stability performance of the photocatalyst was evaluated by comparing the degradation efficiency and the consistency of PXRD patterns before and after cyclic tests. After each cycle, the sample was cleaned with deionized water and dried. As shown in research ,32, the Zn-MOF does not have DMPO∙OH and DMPO∙O2− signals. However, the typical DMPO∙OH  spectroscopy with the trapping agent 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and further investigated their photocatalytic properties, which provided support for the catalytic mechanism. As shown in  DMPO∙OH a and DMPO∙OH , which proved that the pores in the structure were relatively concentrated [Zn-MOF were 11.4087 m2/g and 44.64 × 10−3 cm3/g, respectively. The photocatalytic degradation can be related to different pathways. Although the small specific surface area and pore size do not provide positive factors for the photocatalytic process, the performance of Zn-MOF could be interpreted based on its textural properties. In addition to the direct photocatalytic degradation of tetracycline molecules absorbed by Zn-MOF, photogenerated electron−hole pairs can generate highly oxidative species such as superoxide anions and hydroxyl radicals. These mobile radicals will indirectly degrade the tetracycline in the surrounding solution. Furthermore, it is speculated that the main non-covalent interactions exhibited by Zn-MOF are O...H and N...H interactions, suggesting that tetracycline molecules can interact with materials through these interactions, which play a key role in the degradation of tetracycline molecules.In order to clearly show the morphological characteristics of entrated . Using tEg (Zn-MOF), electrons (e−) in the valence band (VB) will be excited and transferred to the conduction band (CB), ultimately causing the vacancy (h+) to remain in the valence band. As shown in Zn-MOF is more favorable than the VB potential of water molecules converting to hydroxyl radicals (2.38 eV vs. NHE) [+) reacting with water molecules to form hydroxyl radicals (·OH). At the same time, the CB potential of Zn-MOF (−1.15 eV) is more negative than the potential of oxygen conversion to superoxide free radicals (−0.33 eV vs. NHE) [−) to react with oxygen to form superoxide free radicals (·O2−). However, from the mechanism diagram, we can also observe that the superoxide radical has a stronger production effect than the hydroxyl radical, which is consistent with the ESR spectrum.In order to more clearly analyze the production and action processes of hydroxyl radicals and superoxide radicals, we proposed a potential photodegradation mechanism based on the association between VB-XPS and UV-vis DRS analysis and ESR profiles. When illuminated by a photon with energy close to or higher than vs. NHE) , resultivs. NHE) , which eZn-MOF. According to the cyclic voltammetry curve  and a bias potential of 0.5 V, the working electrode exhibited a significant photoelectric response behavior , 5-(2-cyanophenoxy) isophthalic acid , 1,2-bis (4-pyridine)-ethane  and H2O (8 mL) was sealed in a 25 mL Teflon-lined reactor at 120 °C for 3 days. When cooled to room temperature, regular crystals of Zn-MOF were obtained [A mixture of Zn(OAc)obtained .The raw materials are all commercially purchased and do not require further purification. The solvents used are all analytical-grade solvents. Subsequently, the ESR was collected with Bruker A300 , and the UV-vis diffuse reflectance spectrum was recorded with Shimadzu UV-2600 UV-vis spectrophotometer . Powder X-ray diffraction (PXRD) patterns were obtained using a Bruker D8 Advance powder diffractometer using Cu-Kα radiation (λ = 1.5418 A) at a scanning rate of 0.2 s/step and a step size of 0.02 (2θ) at 40 kV and 40 mA.Zn-MOF via the bacteriostatic zone method. Gram-negative bacteria (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus) were selected as research objects to measure Zn-MOF antibacterial performance. The diffusion of the sample in the solid culture substrate was used to inhibit the growth of bacteria and form a transparent circular bacteriostatic zone centered around it.This work evaluates the antibacterial effect of Zn-MOF sample was ground and dispersed in dimethyl sulfoxide (DMSO), and 6 mm circular filter paper with a diameter of pre-sterilized bacteria was placed in the prepared Zn-MOF solution. Then, under aseptic conditions, the prepared LB (Luria–Bertani) solid medium plate was placed on the ultra-clean worktable next to the flame of the alcohol lamp. A total of 50 µL bacteria solution was absorbed and added to the LB solid medium. The bacteria solution was evenly coated with the sterilized coating stick, the filter paper soaked in LB liquid medium, and the filter paper soaked in Zn-MOF solution was removed with tweezers. Finally, the sealed medium plate was placed in a constant temperature incubator at 37 °C. After about 18 h of culture, it was taken out. A Vernier caliper was used to measure the diameter (in three directions) of the bacterial-inhibition zone centered on the sample, and its average value was taken as the experimental result.Firstly, the prepared Zn-MOF on tetracycline was evaluated by using a 300 W xenon lamp equipped with a 420 nm filter to simulate the degradation of tetracycline. Firstly, the catalyst reached absorption–desorption equilibrium under dark conditions. The experimental method involved dispersing the ground photocatalyst (50 mg) in a tetracycline aqueous solution (20 ppm L−1) and stirring continuously for 60 min under dark conditions. Then, the reaction solution was exposed to visible light, and the reaction solution (3 mL) was removed every 5 min and filtered through the filter head of a disposable PES filter with a diameter of 0.45 μm. The supernatant was then collected for UV analysis. The tetracycline concentration was monitored by measuring the absorption intensity of the maximum absorption wavelength (λ = 357 nm) with a Hitachi UV-visible spectrophotometer . Pollutant decomposition efficiency (η) [The photocatalytic performance of C0, where C is the concentration of pollutants during irradiation. In order to evaluate the stability and reusability of Zn-MOF, cyclic photodegradation experiments were performed, and followed the same process as above. At the end of each cycle, the catalysts were collected via centrifugation, washed with deionized water and anhydrous ethanol, and dried under the same conditions for use in the next antibiotic degradation.The concentration of pollutants after adsorption equilibrium is represented by Zn-MOF, the photoelectric properties of the material were evaluated. The tests were performed on a CHI 660E electrochemical analyzer. In the standard three-electrode system, Zn-MOF powder-modified indium tin oxide (ITO) was used as the working electrode. The electrode coating area was 1.0 cm2. A platinum wire electrode was used as the auxiliary electrode, Ag/AgCl was used as the reference electrode and 0.5 M Na2SO4 aqueous solution was used as the electrolyte. The system was carried out in a quartz glass reactor of about 50 cm3 and used a 300 W xenon lamp as a light source.In order to investigate the photoelectric ability of Zn-MOF has been explored with regard to antibacterial properties, photocatalytic tetracycline degradation and photoelectric activity. Zn-MOF has an inhibitory effect on Escherichia coli and Staphylococcus aureus, the zinc ions in which can disturb the bacterial environmental metal balance and destroy the ion channels in the membrane. For tetracycline, Zn-MOF exhibits recyclable photocatalytic degradation. ESR testing demonstrates the importance of the production of active substances for photodegradation. At the same time, BET, SEM, UV-vis, VB-XPS and ESR spectra jointly explained the mechanism of photocatalytic degradation of tetracycline. Finally, the photoelectronic measurement results show that the Zn-MOF-modified electrode can produce higher photocurrent density under negative voltage response, and the photocurrent with adjustable frequency can be obtained by changing the lighting period of the switch and maintaining a certain intensity. This study provides a new perspective for exploring the development of MOF materials in antimicrobial, degradation and photoelectric directions.In summary, the multifunctional nature of


IntroductionThis prospective observational study reports the association between baseline high-sensitivity C-reactive protein (hs-CRP) levels and adverse events at six months in patients who were diagnosed with symptomatic chronic stable angina and then underwent percutaneous transluminal coronary angioplasty (PTCA) with a drug-eluting stent (DES).MethodsA total of 104 patients were examined with chronic stable angina over a period of six months. Before conducting percutaneous coronary intervention (PCI), the baseline levels of hs-CRP were measured, and based on the levels, the patients were grouped into high and low hs-CRP groups.ResultsThe primary causes of death or the need for repeat revascularization or myocardial infarction or angina were concluded after assessing the patients for six months. A total of 104 patients were studied, among which 72 (69.23%) had low hs-CRP and 32 (30.77%) had high hs-CRP levels. The number of males in this study was 68 (65.38%) and females were 36 (34.62%). The mean age of the patients was 55.26 ± 10.31 years. There were no significant differences among the groups in terms of gender, age, comorbidities, and risk factors except for certain predisposing factors like dyslipidemia and smoking. Moreover, we did not find any significant difference among the groups in the cause of death and myocardial infarction after a follow-up of six months. However, we observed a higher need for revascularization and angina outcomes in the group with high hs-CRP compared to low hs-CRP.ConclusionIt can be concluded that a higher risk of angina and repeat revascularization is related to a high baseline hs-CRP but there is no evidence whether it is somehow linked to myocardial infarction and mortality or not. Coronary artery disease (CAD) is one of the major causes of morbidity and death in industrialized and developing countries ,2. The pThis prospective observational study was conducted for a period of one year in the department of cardiology in a tertiary care center at Atal Bihari Vajpayee Institute of Medical Sciences (ABVIMS) and Dr. Ram Manohar Lohia (RML) Hospital, New Delhi. The inclusion criteria for this study were patients with symptomatic chronic stable angina who underwent percutaneous transluminal coronary angioplasty (PTCA) with a drug-eluting stent. Informed consent was obtained from all patients. The exclusion criteria included patients with a history of prior revascularization, acute coronary syndrome (unstable angina (USA), ST-elevation myocardial infarction (STEMI), and non-STEMI (NSTEMI)), with current infection, on current treatment for malignancy, with acute stroke or acute limb ischemia, and usage of immunosuppressive drugs. Prior to intervention, hs-CRP levels were measured in fasting blood samples by using an enzyme-linked immunosorbent assay (ELISA) kit called a Calbio kit  with a sensitivity range of 0.01 to 10 mg/l. The enrolled patients underwent PTCA with a drug-eluting stent (DES). They were subjected to complete revascularization with percutaneous coronary intervention (PCI) in all major arteries. All patients received optimal medical therapy based on the evidence. The clinical follow-ups were sincerely done at two weeks, one month, three months, and six months. During the six-month study duration, all the major events, such as myocardial infarction, repeat revascularization, angina, and mortality, were recorded as endpoints.There were a total of 123 patients enrolled in this study. But the results of the study were based on 104 patients since 19 patients lost follow-up. The patients enrolled for the study were divided into two groups based on the median levels of CRP i.e., high CRP levels >3 mg/l and low CRP levels <3 mg/l. Out of 104 patients, 32 (30.77%) were placed in the high hs-CRP group and 72 (69.23%) were in the low hs-CRP group  male and 36 (34.62%) female patients were studied  and age P=>0.54) between the two groups  and smoking (P=>0.005) between the two groups Tables , 7. and smokAll the enrolled patients had a normal range of hemoglobin and kidney function test levels. In each group, one death was reported in this study due to sudden cardiac arrest leading to deaths. Though no particular cause of death was identified. We did not observe any statistically significant difference between the two groups (P=>0.523). Angina was reported in seven (6.73%) patients. The number of angina patients in the high hs-CRP group, i.e. five (15.63%) was significantly higher than the low hs-CRP group, i.e. two 2.78%) (P=>0.027)  patients in total, out of which one 1.39%) was in the low hs-CRP group and three (9.38%) were in the high hs-CRP group, though this is not statistically significant (P=>0.085). Six (18.75%) patients in the high hs-CRP group and two (2.78%) patients in the low hs-CRP group underwent repeat revascularization during the period of six months of follow-up, which was statistically significant (P=>0.010)  smokers in this study, which included 18 (56.25%) in the high hs-CRP group and 20 (27.78%) in the low hs-CRP group (P =>0.005). This clearly highlights that patients with a history of smoking had high baseline levels of hs-CRP. A similar conclusion was also reported by de Winter RJ et al., where they found the smokers in the study had an increased CRP level of >3 mg/L and were mostly elderly women . AnotherChronic stable angina was reported in seven (6.73%) patients, acute coronary syndrome  in four (3.8%) patients, and death in two 1.92%) patients during follow-up. We evaluated the seven patients with symptoms of chronic stable angina on the treadmill and found five out of seven had high baseline levels of hs-CRP and the levels of the other two patients were normal. This gives a clear indication of the association of high baseline hs-CRP levels with the risk of chronic stable angina. In another study by Antonino Buffon et al., 219 consecutive patients were studied who underwent PTCA on a single non-occlusive coronary stenosis . They re2% patienIn this study, there were eight 7.69 %) patients who underwent repeat revascularization at the time of the six months follow-up. Six (18.75%) patients out of 32 with high levels of hs-CRP underwent revascularization compared to only two (2.78%) out of 72 in the low hs-CRP group. The data obtained were statistically significant (P=>0.010), thus indicating that a higher rate of revascularization is associated with high baseline levels of hs-CRP in patients. A similar outcome was also reported by de Winter RJ et al. who found patients with elevated levels of hs-CRP had an increased rate of revascularization, though the data was statistically insignificant  % patien. It was A study on 1458 consecutive patients who underwent elective coronary angioplasty for Braunwald class I/II/III angina was conducted by de Winter RJ, where the patients were followed up for 12 to 14 months . In thisLimitations of the study This was a single-center study with a small sample size. Multiple confounding factors were not addressed systematically and then impacts on outcomes were not evaluated, for example, smoking, dyslipidemias, diabetic control, hypertension control, and drug compliance. However, in patients with multi-vessel PCI, we could not exclude the effects of "one-sitting PCI vs staged PCI". Recently, there is a controversy about which procedure is superior, one-sitting PCI or staged PCI in multi-vessel disease.Echoing the findings of previous studies, we conclude that higher levels of hs-CRP pose a risk for recurrent event rate and predicting acute events in the future. Further studies are required with a larger sample size, longer follow-up, and the inclusion of various factors to build a concrete conclusion.


Thus, we posit that our methodology is a promising approach to analyze the dynamics of infectious disease outbreaks, and that our forecasts could contribute to designing effective pandemic-arresting public health policies.The rapid spread of the numerous outbreaks of the coronavirus disease 2019 (COVID-19) pandemic has fueled interest in mathematical models designed to understand and predict infectious disease spread, with the ultimate goal of contributing to the decision making of public health authorities. Here, we propose a computational pipeline that dynamically parameterizes a modified SEIRD (susceptible-exposed-infected-recovered-deceased) model using standard daily series of COVID-19 cases and deaths, along with isolated estimates of population-level seroprevalence. We test our pipeline in five heavily impacted states of the US  between March and August 2020, considering two scenarios with different calibration time horizons to assess the update in model performance as new epidemiologic data become available. Our results show a median normalized root mean squared error (NRMSE) of 2.38% and 4.28% in calibrating cumulative cases and deaths in the first scenario, and 2.41% and 2.30% when new data are assimilated in the second scenario, respectively. Then, 2-week (4-week) forecasts of the calibrated model resulted in median NRMSE of cumulative cases and deaths of 5.85% and 4.68% (8.60% and 17.94%) in the first scenario, and 1.86% and 1.93% (2.21% and 1.45%) in the second. Additionally, we show that our method provides significantly more accurate predictions of cases and deaths than a constant parameterization in the second scenario (The online version contains supplementary material available at 10.1007/s00366-023-01816-9. The detection of the first cases of the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) in Wuhan (China) in December 2019 marked the onset of the coronavirus disease 2019 (COVID-19) pandemic –8. TheseMathematical models in epidemiology can be classified into two broad paradigms: statistical and mechanistic. Statistical models usually consist of purely empirical formulations based on a set of predetermined mathematical functions that match the global trend of the observations registered in epidemiological data series  , 15. OthHybrid approaches have been developed to overcome the limitations of the classic statistical and mechanistic modeling paradigms . Using dIn this work, we present a data-informed methodology to perform the dynamic parameterization of a modified SEIRD (Susceptible-Exposed-Infected-Recovered-Deceased) model of COVID-19 spread that has been previously used to reproduce early outbreaks in Italy, Brazil, and the US , 28, 46.ument}D) . Additioument}D) –54. The The remainder of this work is organized as follows. Section We focus on five of the most impacted states in different regions of the US in terms of total confirmed case numbers by late-summer 2020: California (CA), Texas (TX), Florida (FL), New York (NY), and Illinois (IL). Standard epidemiological population variables describing the evolution of the COVID-19 pandemic in the US at the state level have been made available in the public domain by the Center for Systems Science and Engineering at Johns Hopkins University (JHU CSSE) . As the nt study , 56. To  of 2020 . Thus, w of 2020 –60, and  of 2020 . Consequp values  as a proWe employ a modified SEIRD-type compartmental model obtained from previous mathematical epidemiology studies designed to recapitulate and forecast the early outbreak of COVID-19 in the Lombardy region of Italy , 27. FigIR model , as wellIR model , 18, 25.ractions , 46. ExpWhile this model was originally posed assuming a constant value for the epidemiological parameters We developed a three-step computational pipeline to perform a data-driven, time-resolved calibration of the SEIRD model and yield accurate short-term forecasts of outbreak progression. This section is divided into three parts respectively describing each of the steps in our computational pipeline, which are also illustrated in Fig. The first step in the computational pipeline consists of performing dynamic mean filtering of rolling weekly parameterizations of the mechanistic model based on daily series of diseases , 61–63. We define a window of length mentclass2pt{minimLet We apply the mean filter defined in Eq.  dynamicaThe first two terms on the right-hand side of Eq.  are the  via Eq.  for the . In Eq. , \documeThe dynamic calibration method described in this section is further cast as a multi-start problem to determine the global optimal time-resolved parameterization of our model over the parameter space defined in Table r in Eq.  can be adatabase . We alsoderation . Thus, wFor any of the subsequent windows starting at day We leverage latin hypercube sampling to generate a set of mentclass2pt{minimmentclasspt{minimaterature –53, 55.We employ B-splines to construct a smooth functional representation capturing the temporal changes in the daily estimates of the model parameters and enabling the extrapolation of these parameter trends to forecast outbreak evolution. B-splines are piecewise polynomial functions that can provide a smooth and flexible framework to represent both simple and complex temporal changes in parameter trends –71. AddiWe calculate the B-spline representation of the time-resolved dynamics of each epidemiological parameter . Each bTo assess the degree of improvement arising from the use of our computational pipeline, we compare the calibration and forecasting results of our dynamic parameterization approach with respect to a standard constant parameterization scheme. Hence, the constant parameterization aims at finding a unique set of epidemiological parameters  , 72. Henument}Sp  . The SEIRD model in Eqs. . Nevertheless, the results in Table During the forecasting interval, the cumulative NRMSE values reported in Table entclass1pt{minima1.10%, 7.8% in theWe investigate the adaptive performance of our computational pipeline as further epidemiological data becomes available in the D166 scenario, where we extend the calibration timeframe by 2 weeks and assimilate the corresponding daily measurements of Figure  2.41% 0.8%, 4.54% 2.41% 0.8%, 4.54% 2.41% 0.8%, 4.54%p = 0.028, 0.048, 0.048, 0.028 for cumulative NRMSEs and p = 0.028, 0.048, 0.048, 0.028 for weekly NRMSEs under one-sided Wilcoxon rank-sum testing, respectively). This improvement in predictive power was also observed in the forecasts of p = 0.048, 0.028, 0.028, and 0.028 for cumulative NRMSEs and p = 0.048, 0.028, 0.028, 0.048 for weekly NRMSEs under one-sided Wilcoxon rank-sum testing, respectively). Nevertheless, the quality of the prediction of p = 0.27, 0.15 for cumulative NRMSEs and p = 0.27, 0.11 for weekly NRMSEs under one-sided Wilcoxon rank-sum testing, respectively).While the calibration performance in the D166 scenario is similar to that observed in the D152 scenario . For example, comparing Figs. −1 across of all epidemiological parameters and states, which contributes to a noticeable change in −1 across all the parameter values. Likewise, on day 166, we obtained an absolute difference of − 0.0096  day−1 across all the parameter values.The assimilation of further data during the dynamic parameterization of the model in the D166 scenario resulted in an update of the daily estimates obtained from the rolling weekly calibration , which further induced an update of the corresponding B-spline fits describing the dynamics of the epidemiological parameters . Supplementary Figures S7 and S8 show the fits and forecasts obtained with this standard calibration method in the D152 and D166 scenarios, respectively, while Supplementary Tables S4 and S5 provide the corresponding NRMSE values. Moreover, Supplementary Figs. S9–S11 compare the NRMSE distributions obtained with the dynamic and constant  parameterization approach during the calibration and forecasting timeframes in the D152 and the D166 scenarios, respectively. Comparing Figs. We have presented a computational pipeline that enables the time-resolved parameterization of a mechanistic model of infectious disease spread to facilitate the recapitulation and forecasting of outbreak dynamics. This approach leverages the idea that it takes a short-to-intermediate timeframe for epidemiological changes to manifest in the case and death numbers reported during an outbreak. Thus, the computational pipeline seeks to capture the dynamic changes in the mechanisms of infectious disease spread through a time-resolved parameterization primarily informed by standard time series of cumulative infections and deaths  describing COVID-19 outbreak dynamics using time series of cumulative infections (Supplementary file1 (DOCX 4046 KB)Below is the link to the electronic supplementary material.


Artemisia vestita, is lethal to many cancer cells and has antioxidant, anticancer, and antibacterial properties. Here, we investigated the underlying mechanisms of the antithrombotic action of CSL. We demonstrated that CSL has antithrombotic efficacy comparable to rivaroxaban, a direct blood coagulation factor Xa (FXa) inhibitor employed as a positive control, in inhibiting the enzymatic activity of FXa and the platelet aggregation induced by adenosine diphosphate (ADP) and U46619, a thromboxane A2 analog. The expression of P-selectin, the phosphorylation of myristoylated alanine-rich C kinase substrate by U46619 or ADP, and the activation of PAC-1 in platelets were inhibited by CSL. Nitric oxide production was increased by CSL in ADP- or U46619-treated human umbilical vein endothelial cells (HUVECs), although excessive endothelin-1 secretion was suppressed. CSL demonstrated strong anticoagulant and antithrombotic effects in a mouse model of arterial and pulmonary thrombosis. Our findings suggest that CSL is a potential pharmacological candidate for a novel class of anti-FXa and antiplatelet medications.A small natural substance called cirsilineol (CSL), which was discovered in the plant  The activation of the intrinsic and extrinsic coagulation systems; adhesion, aggregation, and secretory functions of activated platelets; and thrombosis (one of the primary causes of death worldwide) are all directly associated with the activation of the coagulation systems . Direct It is essential to conduct significant clinical trials on the correlation between anticoagulant and antiplatelet drugs. For example, the AGUSTUS study revealed that the addition of a Cox-1 inhibitor and P2Y12 inhibitor to the Xa antagonist offered an initial advantage but ultimately resulted in excessive bleeding , and it Notably, several thromboembolic illnesses are also significantly impacted by platelet aggregation. Platelets are crucial for hemostasis and the beginning and continuing stages of thrombus development . InhibitArtemisia vestita (Asteraceae). CSL is a powerful anti-inflammatory, hypnotic, anticancer, antibacterial, and anti-anxiety medication that demonstrates cytotoxicity against several cancer cells i were inhibited by CSL administration , a significant phosphorylation substrate of PKC in human platelets. Both protein kinase C (PKC) activation and an increase in cytosolic Caregation . Indeed,ectively . Ca2+ anregation . ADP- anstration B,C. Our P-selectin is translocated to the exterior membrane when platelets are activated, and fibrinogen connects PAC-1 between adjacent platelets, causing aggregation . Figure An important endogenous vasodilator, NO prevents platelet aggregation and protects the arterial wall. A potent vasoconstrictor called ET-1 is produced from the vascular endothelium and secretes NO ,33,34. TSeveral medications that reduce platelet aggregation are now widely used to treat thrombotic diseases alone or in conjunction with other medicines that inhibit platelets. However, their long-term usage is regularly known to have adverse effects ,38. Our Platelet aggregation and clotting time are the most often utilized criteria for assessing the effectiveness of novel antithrombotic medications . In our 2+ mobilization, and P-selectin and PAC-1 expression levels. Therefore, CSL has antiplatelet potential by inhibiting platelet aggregation, coagulation times, cytosolic Ca2+ mobilization, FXa activation and generation, the phosphorylation of MARCKS through the PKC pathway, and the expression of P-selectin and PAC-1. Additionally, CSL decreased the synthesis of ET-1, a vasoconstrictor, and improved the secretion of the NO vasodilator. The activation, adhesion, and aggregation processes of platelets are involved in the mechanism that causes the coagulation event i) of platelets was measured as previously described i by measuring the intensity of fluorescence signals (excitation/emission wavelengths: 339/500 nm) obtained from the platelets.The amount of intracellular Caescribed . A finalz et al.  proposed8 platelets/mL) for 3 min. The platelet suspension was refrigerated at 4 °C after stimulation with ADP (10 μM) or U46619 (6 μM) for 6 min at 37 °C. Subsequently, 50 μL of the sample was mixed with activation-specific anti-PAC-1 and anti-CD61-PE in saturated concentrations, and the mixture was then incubated for 25 min in the dark to determine the expression of PAC-1. Anti-CD62P-PE and anti-CD61-FITC were combined with 50 μL of the sample and incubated for 25 min in the dark to determine the expression of P-selectin. Samples that had been quench-diluted (<4-fold) were examined using a flow cytometer . Populations of platelets were gated on cell size with forward scatter vs. side scatter and CD61 positivity to distinguish platelet populations from background noise. Finally, 5000 events were evaluated for each sample. The mean fluorescence intensities from each channel were expressed using BD Accuri C6 software . Five distinct samples of donors were used for the measurements.PAC-1 and P-selectin expression levels were assessed by modifying accepted techniques . BrieflyA commercially available ELISA kit was used to measure the generation of NO and ET-1  in the cell culture medium.3-induced thrombosis was created and used. Male C57BL/6 mice were starved for the entire night before receiving intravenous injections of the relevant drug in 0.2 mL of DMSO and were allowed to sleep. The carotid artery of the animal was exposed. The adventitial surface was covered with a cotton thread (200 μm in diameter) soaked in FeCl3 solution (0.25 M) for 5 min. The wound was flushed with saline solution once the thread had been removed. The development of thrombus was observed at 35 °C using 3D imaging. We measured the size and rate of thrombus formation, and we graded our results as follows: no thrombus or small thrombus (75–50 μm), medium thrombus (150–100 μm), massive thrombus (300–200 μm), and more than three thrombi. It was also noted how long it took for an extensive thrombus to obstruct the carotid artery following endothelial damage caused by FeCl3.A mouse model of FeCl2 lung field as previously described [Mice were separated into several groups after being fasted overnight . CSL was dissolved in DMSO and given intravenously to each mouse. After 1 h, the animals received an injection of collagen and epinephrine mixture (500 μg/kg each) to induce acute thrombosis ,55. Eachescribed .p-value of <0.05 was considered statistically significant.The data are presented as the mean value ± standard deviation (SD) of five separate experiments conducted in duplicate. Tukey’s tests were run as a post-hoc examination of the differences between the various groups after one-way analysis of variance revealed a significant difference between the groups. A


In the current EEG study, we used a dot-probe task in conjunction with backward masking to examine the neural activity underlying awareness and spatial processing of fearful faces and the neural processes for subsequent cued spatial targets. We presented face images under different viewing conditions  and manipulated the relation between a fearful face in the pair and a subsequent target. Our mass univariate analysis showed that fearful faces elicit the N2-posterior-contralateral, indexing spatial attention capture, only when they are presented supraliminally. Consistent with this, the multivariate pattern analysis revealed a successful decoding of the location of the fearful face only in the supraliminal viewing condition. Additionally, the spatial attention capture by fearful faces modulated the processing of subsequent lateralised targets that were spatially congruent with the fearful face, in both behavioural and electrophysiological data. There was no evidence for nonconscious processing of the fearful faces in the current paradigm. We conclude that spatial attentional capture by fearful faces requires visual awareness and it is modulated by top-down task demands. Specifically, we may express fear in response to dangerous events or threat. Therefore, fearful faces are usually perceived as indicators of negative events and they tend to attract our attention easily . It has With regards to attentional capture, it has been shown that the presence of a fearful face can enhance the processing of a subsequent stimulus. Such modulatory effects of fearful faces on subsequent targets have been mainly examined using the dot-probe paradigm e.g., . In thisNeural imaging studies have provided supporting evidence for these behavioural observations. For example, in a dot-probe experiment using electroencephalography (EEG) recording, In an object-substitution masking study by In a series of backward masking experiments, we analysed ERPs for fearful faces presented in face pairs with different visibility  or for a longer time (166 ms) and immediately backward masked. A following lateralised dot either appeared on the same side as the fearful face (congruent) or on the side opposite to it (incongruent). In one half of the experiment, the participants were required to respond to the target dots as well as the faces that preceded them, whereas in the other half of the experiment, participants were instructed to ignore the faces.For the face stimuli, we expected to find an N2pc for the fearful face only in the supraliminal viewing condition, replicating our previous finding . For the2.2.1.p2η = 0.22; ageM = 21.9, ageSD = 2.1, 8 males, 18 females). This study was approved by the University of Queensland ethics committee.We determined the sample size in MorePower  using an2.2.The experiment was programmed and run in PsychoPy 3  and all Face stimuli were obtained from the Radboud Face Database . We usedA white disc (a dot) extending 0.25°x 0.25 in visual angle was used as the target stimulus in the current dot-probe paradigm . The disAll images were rendered black-and-white and were presented on a black screen. Image editing was performed in Adobe Photoshop (version 22.4.0).2.3.As shown in There were two types of blocks in the experiment: face-relevant and face-irrelevant blocks. In the face-relevant blocks, participants were instructed to first perform the dot localisation task. Then, they were required to indicate on which side of the screen they saw a fearful face  with their left hand. In the face-irrelevant blocks, participants were instructed to respond only to the dots and ignore the faces. That is, they only needed to perform the speeded dot localisation task in these blocks. Each of the face combinations was presented equiprobably in all conditions, and the dot presentations were manipulated orthogonally to the face presentations.congruent condition, where the fearful face and the subsequent dot were presented on the same side of the screen, incongruent condition, where they were presented on different sides of the screen and the control condition where the two neutral faces were presented before the dot.There were three conditions regarding the location of the fearful face and the lateralised dot in each trial: There were 16 blocks of 1,200 trials  in total with short breaks provided between blocks. Participants completed eight face-relevant blocks in either the first half or the second half of the experiment and completed the eight face-irrelevant blocks in the other half of the experiment. This order was determined randomly by the experimental programme for each participant.2.4.Raw continuous EEG was recorded at 1024 Hz using the BioSemi ActiveTwo system . Sixty-four electrodes were placed according to the international 10–20 system location. Horizontal electrooculogram (EOG) was recorded with two bipolar electrodes. Vertical EOG was recorded with an external electrode placed below participants’ left eye. Recordings were referenced online to the CMS/DRL electrodes.N = 26).Pre-processing of the EEG data was performed with EEGLAB  and ERPL2.5.M = 0.96, SD = 0.03). For the fearful face localisation task, we examined the accuracy data with a paired-samples t-test. All behavioural data analyses were performed in IBM SPSS Statistics 27.At the behavioural level, we examined the reaction time data from the speeded dot localisation task with a repeated-measures ANOVA. We only used reaction time data from the task-correct trials and excluded datapoints identified as outliers from an outlier cheque  for each participant. We did not analyse the accuracy data for the dot localisation task because the accuracy was near ceiling . Follow-up comparisons were conducted using the cluster-based permutation t-tests (two-tailed family-wise α = 0.05).Because we were interested in the early visual processing of the stimuli, posterior electrodes were selected as regions of interest. Only lateral electrodes were included in ERP analyses due to the lateralised stimulus configuration. As a result, the electrodes of interest are P3/4, P5/6, P7/8, P9/10, PO3/4, PO7/8 and O1/2. For significant difference testing, we performed the cluster-based permutation test  on all time-points within the epoch (0-600 ms), with a family-wise α level of 0.05. Electrodes were considered as spatial neighbours if adjacent electrodes were within 3.3 cm from each other , we collapsed the left and right electrodes and retained the information about the relation between the location of the fearful face and electrodes. Specifically, in the two fearful-face-present conditions, signals were relabelled based on whether they were contralateral or ipsilateral to the fearful face. For the neutral faces condition, the average signals between the left and right electrodes were calculated.For the analyses on the dot-related signals, we first subtracted signals in the dot-absent baseline trials from the dot-present trials to remove effects from the preceding face stimuli. Specifically, the ERPs time-locked to the dot onset from the baseline condition would be subtracted from the ERPs from the experimental condition  that was preceded by the same face combination . Then, we averaged signals from the left and right electrodes. Analyses were performed on the average baseline-subtracted ERPs.2.5.2.t-tests (against chance-level decoding performance at 50%). The t statistics were corrected for multiple comparisons using Threshold-Free Cluster Enhancement (TFCE) and Monte Carlo-based permutations  for each condition of face-visibility (collapsing across face-relevancy), and decoded the fearful face location for each condition of face-relevancy (collapsing across face-visibility). All signals were time-locked to the face onset.For the dot-related signals, we performed decoding of fearful-face-dot congruency (congruent vs. incongruent) across all conditions and also separately for the face-subliminal and face-supraliminal conditions. All signals were time-locked to the dot onset.3.3.1.3.1.1.t-test on the accuracy data (percent correct) for the fearful face localisation task revealed that the fearful face was more accurately localised in the supraliminal condition  than the subliminal condition , t(25) = 10.51, p < 0.001, d = 2.06. A one-sample t-test showed that the accuracy in the subliminal condition was not different from chance-level performance (0.33), t(25) = 0.92, p = 0.368.A paired-samples 3.1.2.F = 28.05, p < 0.001, p2η = 0.53), a main effect of face-relevancy  = 92.63, p < 0.001, p2η = 0.79) and a significant interaction between the two, F = 27.01, p < 0.001, p2η = 0.52. Specifically, participants were faster at localising the dot in the face-irrelevant condition  than face-relevant condition , and when the preceding faces were presented subliminally  than when presented supraliminally . The effect of face-relevancy was significant in both face-visibility conditions, ps < 0.001. However, the effect of face-visibility was significant only when the faces were task-relevant, p < 0.001. When participants did not need to attend to the faces, no difference was found between face-subliminal and face-supraliminal conditions, p = 0.295.A 3(fearful-face-dot congruency) x 2(face-visibility) x 2(face-relevancy) repeated-measures ANOVA on the reaction times (in seconds) revealed a significant main effect of face-visibility  = 22.92, p = 0.008, p2η = 0.20. Follow-up tests showed that, the effect of congruency was non-significant in the face-subliminal condition, F = 1.33, p = 0.274, but was significant in the face-supraliminal condition, F = 3.98, p = 0.025, p2η = 0.14. As part of our planned comparisons, the levels of congruency were compared against each other in the face-supraliminal condition. We found that, the dot was localised significantly slower in the incongruent condition, compared to the congruent condition, p = 0.023, and the control condition, p = 0.018. The difference between congruent and control conditions was non-significant, p = 0.508. No other effect was significant, Fs < 2.25, ps > 0.116.The interaction between face-visibility and congruency was also significant, 3.2.3.2.1.Fs > 3.19, ps < 0.001. As shown in For ERPs time-locked to the face stimuli, we collapsed the left and right electrodes to create the laterality variable which indicates the relation between the location of a fearful face and the electrodes. A 3 x 2 x 2 repeated-measures ANOVA revealed that all main effects were significant, Fs > 3.19, ps < 0.009. Follow-up tests revealed that the effect of laterality was significant only in the supraliminal conditions. Thus, we compared three levels of laterality against each other in the supraliminal condition, separately for face-relevant and face-irrelevant conditions, using the cluster-based permutation t-tests.All interaction effects were significant including the three-way interaction between laterality, face-visibility and face-relevancy, When the supraliminally-presented faces were task-irrelevant, signals contralateral to the fearful face were more negative than ipsilateral signals between 203–297 ms at posterior electrode sites , again reflecting an N2pc for the target fearful face, and a later time window, 477-600 ms , see Importantly, the later negativity between 477–600 ms in the contralateral-ipsilateral contrast  likely rTo summarise, starting from 113 ms post-face-onset, significant effects of all three variables of interest  were found on the ERPs, encompassing time windows of the N2pc and the SPCN.3.2.2.Fs > 4.26, ps < 0.028.For ERPs time-locked to the target dots, because we did not have a hypothesis about the contralateral and ipsilateral signal differences, we averaged signals from the left and right electrodes, regardless of the spatial relation between the target and the electrodes , separately for when the faces were presented subliminally and when presented supraliminally.When the preceding faces were presented subliminally, there was a significant negative cluster between 246–445 ms across electrodes P7/8, PO3/4, PO7/8, P9/10 and O1/2 with the maximal effect found on O1/2 , see When the preceding faces were presented supraliminally, there was a significant positive cluster between 195–328 ms across all posterior electrodes with the maximal effect found on P3/4 . In a later time window of 324-445 ms, signals in the face-relevant condition continued to be attenuated, compared to face-irrelevant condition, see F = 3.22, p = 0.042. A simple effect test revealed that the congruency effect was significant only in the face-relevant condition, F = 3.18, p = 0.031. As part of our planned comparisons, we compared levels of congruency  against each other at each level of face visibility, in the face-relevant condition.From the omnibus analysis on dot-related signals, the main effect of congruency was not significant. However, the interaction between congruency and face-relevancy was significant see , F = 3.2When the faces were presented subliminally, there were no significant differences in any of the comparison pairs. However, when the faces were presented supraliminally, signals in the incongruent condition were more negative than in the congruent condition between 258–383 ms , see To summarise, modulations of all three variables  were found on the mid-latency ERPs. Notably, the effect of congruency was significant only in the face-visible and face-relevant condition.3.3.3.3.1.SEM = 0.72) between 270–289 ms. However, the decoding accuracy was at chance-level in the subliminal conditions  in the subliminal and supraliminal conditions, separately, using signals time-locked to the onset of the face stimuli. The decoding was successful only in the supraliminal conditions  and between 123 and 150 ms  , compared to when they were presented at locations opposite the fearful face (incongruent condition). Behaviourally, we found evidence for this cue validity effect, again only when the preceding face stimuli (cues) were presented supraliminally and when they were task-relevant. These results are consistent with numerous reports of the facilitatory effects of an emotional face on validly cued stimuli . These results are not surprising as the top-down suppression of task-irrelevant signals have been demonstrated extensively in the literature e.g., . As explThe task-relevancy of the faces also modulated the processing of the following target dot in the current paradigm. Specifically, a pair of task-relevant faces weakened the overall neural activity for the subsequent targets, regardless of the visibility of the faces. Perhaps, the dual task demands resulted in a higher attentional load in the face-relevant condition. Specifically, the task-relevant faces required a certain amount of the limited attentional or working memory resources  that areFinally, and most importantly, no evidence was found for the nonconscious processing of fearful faces in the current paradigm. This was supported by both the univariate and multivariate analysis results, and through two indices of spatial attention . Indeed, no N2pc for fearful faces was observed in the subliminal viewing condition, and the neural processes for the dots following subliminal face presentations were not modulated by the presence of a fearful face. Consistent with this, the MVPA decoding performance for the spatial location of the fearful faces was at chance-level when the faces were presented subliminally. Additionally, no successful decoding of congruency was found in the face-subliminal condition. Thus, in a bilateral presentation of face images, the spatial information about a lateralised fearful face cannot be processed without visual awareness. This finding is consistent with our recent studies , 2023 anThe majority of studies showing evidence for the nonconscious processing of fearful faces used central face presentations e.g., . Faces pThe use of bilateral presentations of faces in other studies on nonconscious emotion processing is however not rare . For exaAnother approach to investigate nonconscious emotion processing is testing patients with cortical blindness. Such patients usually experience a loss of visual awareness due to regional lesion(s) in the brain. Previous clinical studies have consistently shown that emotional faces can be processed even though the patients were incapable of detecting or reporting the stimuli  for attentional capture by fearful faces.https://osf.io/54nw2/.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: The studies involving human participants were reviewed and approved by University of Queensland ethics committee. The patients/participants provided their written informed consent to participate in this study.ZQ and AP contributed to conception and design of the study. ZQ and JJ collected data and performed data processing. ZQ performed data analyses and wrote the first draft of the manuscript. ZQ, SB, and AP contributed to manuscript revision. All authors contributed to the article and approved the submitted version.ZQ was supported by UQ PhD scholarships.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.